tbuckley/cabot-search huggingface dataset:
The RAGE/DIAPH1 axis: mediator of obesity and proposed biomarker of human cardiometabolic disease
Authors: Lakshmi Arivazhagan, Collin J Popp, Henry H Ruiz, Robin A Wilson, Michaele B Manigrasso, Alexander Shekhtman, Ravichandran Ramasamy, Mary Ann Sevick, Ann Marie Schmidt
Journal: Cardiovascular Research (2022)

Abstract Overweight and obesity are leading causes of cardiometabolic dysfunction. Despite extensive investigation, the mechanisms mediating the increase in these conditions are yet to be fully understood. Beyond the endogenous formation of advanced glycation endproducts (AGEs) in overweight and obesity, exogenous sources of AGEs accrue through the heating, production, and consumption of highly processed foods. Evidence from cellular and mouse model systems indicates that the interaction of AGEs with their central cell surface receptor for AGE (RAGE) in adipocytes suppresses energy expenditure and that AGE/RAGE contributes to increased adipose inflammation and processes linked to insulin resistance. In human subjects, the circulating soluble forms of RAGE, which are mutable, may serve as biomarkers of obesity and weight loss. Antagonists of RAGE signalling, through blockade of the interaction of the RAGE cytoplasmic domain with the formin, Diaphanous-1 (DIAPH1), target aberrant RAGE activities in metabolic tissues. This review focuses on the potential roles for AGEs and other RAGE ligands and RAGE/DIAPH1 in the pathogenesis of overweight and obesity and their metabolic consequences.
Self-immolative nanosensitizer for glutathione depletion- assisted sonodynamic therapy
Authors: Chan Ho Kim, Dong Gil You, Pramod Kumar E. K., Kyung Hee Han, Wooram Um, Jeongjin Lee, Jae Ah Lee, Jae Min Jung, Heegun Kang, Jae Hyung Park
Journal: Theranostics (2022)

Background: Despite remarkable advances in sonodynamic therapy (SDT) of cancer, the low reactive oxygen species (ROS) quantum yield of the sonosensitizer remains a critical concern in glutathione (GSH)-overexpressing cancer cells.Methods: For enhanced SDT, we report hydrophilized self-immolative polymer (SIP)-decorated TiO2 nanoparticles (HSIPT-NPs) to achieve on-demand GSH depletion and ROS generation.Results: Upon intracellular delivery of HSIPT-NPs into hydrogen peroxide-rich cancer cells, SIP is degraded through electron transfer to produce GSH-depleting quinone methide, reprogramming GSH high cancer cells into GSH low phenotype.In the presence of ultrasound, compared to conventional TiO2 NPs, HSIPT-NPs induce significantly higher oxidative stress to cancer cells by incapacitating their antioxidant effects.SDT with HSIPT-NPs effectively inhibit tumor growth in mice via the synergistic effects of GSH depletion and ROS generation. Conclusion:On the basis of their ability to reprogram cancer cells, HSIPT-NPs offer considerable potential as a nanosensitizer for enhanced SDT.
Hybrid core-shell particles for mRNA systemic delivery
Authors: Valentina Andretto, Mathieu Repellin, Marine Pujol, Eyad Almouazen, Jacqueline Sidi-Boumedine, Thierry Granjon, Heyang Zhang, Katrien Remaut, Lars Petter Jordheim, Stéphanie Briançon, Isabell Sofia Keil, Fulvia Vascotto, Kerstin C. Walzer, Ugur Sahin, Heinrich Haas, David Kryza, Giovanna Lollo
Journal: Journal of Controlled Release (2022)

mRNA based infectious disease vaccines have opened the venue for development of novel nucleic acids-based therapeutics. For all mRNA therapeutics dedicated delivery systems are required, where different functionalities and targeting abilities need to be optimized for the respective applications. One option for advanced formulations with tailored properties are lipid-polymer hybrid nanoparticles with complex nanostructure, which allow to combine features of several already well described nucleic acid delivery systems. Here, we explored hyaluronic acid (HA) as coating of liposome-mRNA complexes (LRCs) to investigate effects of the coating on surface charge, physicochemical characteristics and biological activity. HA was electrostatically attached to positively charged complexes, forming hybrid LRCs (HLRCs). At different N/P ratios, physico-chemical characterization of the two sets of particles showed similarity in size (around 200 nm) and mRNA binding abilities, while the presence of the HA shell conferred a negative surface charge to otherwise positive complexes. High transfection efficiency of LRCs and HLRCs in vitro has been obtained in THP-1 and human monocytes derived from PBMC, an interesting target cell population for cancer and immune related pathologies. In mice, quantitative biodistribution of radiolabeled LRC and HLRC particles, coupled with bioluminescence studies to detect the protein translation sites, hinted towards both particles' accumulation in the hepatic reticuloendothelial system (RES). mRNA translated proteins though was found mainly in the spleen, a major source for immune cells, with preference for expression in macrophages. The results showed that surface modifications of liposome-mRNA complexes can be used to fine-tune nanoparticle physico-chemical characteristics. This provides a tool for assembly of stable and optimized nanoparticles, which are prerequisite for future therapeutic interventions using mRNA-based nanomedicines.
A Pro-Regenerative Environment Triggers Premalignant to Malignant Transformation of Senescent Hepatocytes
Authors: Anna Wuestefeld, Viktoriia Iakovleva, Shirlyn Xue Ling Yap, Agnes Bee Leng Ong, Daniel Q. Huang, Timothy Wai Ho Shuen, Han Chong Toh, Yock Young Dan, Lars Zender, Torsten Wuestefeld
Journal: Cancer Research (2022)

Abstract Unfortunately, available liver cancer treatments are associated with modest survival advantage. The biggest factor improving survival is early detection, but the current understanding of early transformation events is limited. Therefore, we set up a model to study these early events and investigated the relationship of premalignant, senescent hepatocytes, a regenerative environment, and the influence of secreted factors on liver tumorigenesis. Oncogene-induced senescence (OIS) was triggered in a subset of mouse hepatocytes, which under normal conditions, are eliminated by immunosurveillance. Inducing liver damage and regeneration was sufficient to trigger immunosurveillance escape of OIS hepatocytes, resulting in premalignant to malignant transformation and hepatocellular tumor development. Trefoil factor 3 (TFF3) was found to be overexpressed in OIS hepatocytes and in hepatocellular carcinoma. TFF3 deficiency strongly attenuated malignant transformation by increasing insulin-like growth factor binding protein 5 (IGFBP5) expression, which consequently dampened IGF receptor signaling. Furthermore, analysis of precancerous liver tissue validated TFF3 as an early liver cancer biomarker. Altogether, these findings provide mechanistic insights into early transformation and immunosurveillance escape in liver cancer, revealing TFF3 and IGFBP5 to be important players with opposite roles in tumorigenesis. Significance: Liver damage induces a compensatory regenerative response that can drive premalignant to malignant transformation of senescent hepatocytes.
Association of Rituximab With Risk of Long-term Cardiovascular and Metabolic Outcomes in Patients With Pemphigus
Authors: Khalaf Kridin, Noor Mruwat, Ralf J. Ludwig
Journal: JAMA Dermatology (2022)

The association of different therapeutic approaches with long-term cardiovascular and metabolic outcomes in patients with pemphigus remains to be precisely evaluated.To assess the risk of long-term cardiovascular and metabolic outcomes and all-cause mortality in patients with pemphigus managed by rituximab compared with those receiving treatment with first-line corticosteroid-sparing agents (azathioprine and mycophenolate mofetil [MMF]).A global population-based retrospective cohort study compared 961 patients with pemphigus that was managed with rituximab with those treated with azathioprine or MMF (n = 961) regarding the risk of several cardiovascular and metabolic outcomes. Propensity score matching was performed to optimize comparability. Patients were enrolled from the Global Collaborative Network of TriNetX platform.Risk of myocardial infarction, stroke, peripheral vascular disease, pulmonary embolism, hypertension, hyperlipidemia, type 2 diabetes, obesity, osteoporosis, and avascular bone necrosis.Of 1602 participants, 855 (53.4%) were women and 747 (46.6%) were men; the mean (SD) age was 54.8 (16.6) years for those treated with rituximab and 54.4 (18.2) years for those treated with azathioprine or MMF. Compared with those treated by azathioprine/MMF, patients treated with rituximab experienced a lower risk of myocardial infarction (relative risk [RR], 0.45; 95% CI, 0.24-0.86; P = .01), stroke (RR, 0.42; 95% CI, 0.26-0.69; P < .001), peripheral vascular disease (RR, 0.47; 95% CI, 0.28-0.79; P = .003), hypertension (RR, 0.48; 95% CI, 0.38-0.63; P < .001), hyperlipidemia (RR, 0.45; 95% CI, 0.32-0.64; P < .001), type 2 diabetes (RR, 0.63; 95% CI, 0.51-0.77; P < .001), obesity (RR, 0.49; 95% CI, 0.34-0.72; P < .001), and osteoporosis (RR, 0.46; 95% CI, 0.30-0.71; P < .001). The all-cause mortality was comparable between patients in both groups (hazard ratio, 0.94; 95% CI, 0.62-1.43; log-rank P = .77).The results of this cohort study suggest that rituximab was associated with protection against long-term cardiovascular and metabolic outcomes compared with conventional immunosuppressants. This agent might be particularly preferred in individuals with preexisting cardiovascular and metabolic risk factors.
Association of Interleukin 6 Inhibition With Ziltivekimab and the Neutrophil-Lymphocyte Ratio
Authors: Nicholas H. Adamstein, Jan Hein Cornel, Michael Davidson, Peter Libby, Alessandra de Remigis, Camilla Jensen, Kathrine Ekström, Paul M Ridker
Journal: JAMA Cardiology (2022)

The neutrophil-lymphocyte ratio (NLR) independently predicts atherosclerotic events and is a potential biomarker for residual inflammatory risk. Interleukin (IL) 1β inhibition reduces the NLR, but whether inhibition of IL-6, a cytokine downstream of IL-1, also lowers the NLR is uncertain.To evaluate whether ziltivekimab, a therapeutic monoclonal antibody targeting the IL-6 ligand, associates with a lower NLR compared with placebo.This was an exploratory post hoc analysis of Trial to Evaluate Reduction in Inflammation in Patients With Advanced Chronic Renal Disease Utilizing Antibody Mediated IL-6 Inhibition (RESCUE), a double-blind, randomized, placebo-controlled, phase 2 trial conducted from June 17, 2019, to January 14, 2020, with 24 weeks of follow-up. Participants were enrolled at 40 sites in the US and included adults aged 18 or older with moderate to severe chronic kidney disease and high-sensitivity C-reactive protein levels of 2 mg/L or greater. Data were analyzed from September 28, 2021, to October 2, 2022.Participants were randomly assigned equally to placebo or ziltivekimab, 7.5 mg, 15 mg, or 30 mg, subcutaneously every 4 weeks.The primary outcome was the change in the NLR at 12 weeks.A total of 264 participants (median [IQR] age, 68 [60-75] years; 135 men [51%]; 129 women [49%]) were enrolled, of which 187 (71%) had diabetes, and 126 (48%) had known atherosclerosis. The median (IQR) change in the NLR at 12 weeks was 1.56% (IQR, -15.7% to 20.0%), -13.5% (IQR, -31.6% to 3.20%), -14.3% (IQR, -26.9% to 4.62%), and -22.4% (IQR, -33.3% to -4.27%) in the placebo, 7.5-mg, 15-mg, and 30-mg groups, respectively. The estimated treatment difference compared with placebo was -14.6% (95% CI, -24.8% to -4.81%; P = .004), -15.3% (95% CI, -25.2% to -5.10%; P = .004), and -23.6% (95% CI, -33.2% to -14.2%; P < .001) in the 7.5-mg, 15-mg, and 30-mg groups, respectively. A similar reduction in the absolute neutrophil count was observed.Results of this post hoc analysis of the RESCUE trial show that IL-6 ligand inhibition with ziltivekimab associates with a lower NLR, suggesting that it may disrupt multiple atherogenic inflammatory pathways, including those mediated by the myeloid cell compartment. The NLR may have use in monitoring ziltivekimab's efficacy should it be introduced into clinical practice.
Paradigm shift in future biophotonics for imaging and therapy: Miniature living lasers to cellular scale optoelectronics
Authors: Paromita Sarbadhikary, Blassan P. George, Heidi Abrahamse
Journal: Theranostics (2022)

Advancements in light technology, devices and its applications have tremendously changed the facets of biomedical science and engineering to provide powerful diagnostic and therapeutic capabilities ranging from basic research to clinics. Recent novel innovations and concepts in the field of material science, biomedical optics, processing technology and nanotechnology have enabled increasingly sophisticated technologies such as cellular scale, wireless, remotely controlled micro device for
Design and reporting of phase III oncology trials with prospective biomarker validation
Authors: Fei Liang, Ling Peng, Zhengyu Wu, Georgios Giamas, Justin Stebbing
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Phase III trials with prospective biomarker validation are essential to drug development in the era of personalized oncology. However, concerns have emerged regarding the design and reporting of phase III trials with prospective biomarker validation. Methods We searched MEDLINE for phase III oncology trials with prospective biomarker validation published in high-impact medical journals from 2011 to 2020. Information regarding trial design and reporting were extracted. Descriptive methods were used to summarize the results. Results We identified 45 phase III trials with prospective biomarker validation. There was a trend for increasing use of biomarker validation phase III trials (from 1 trial in 2011 to 12 trials in 2020). For 39 (86.7%) trials, results in biomarker-negative population were either listed as an exploratory subgroup analysis (62.2%) or not mentioned in the methods (24.4%). Twenty-one (46.7%) trials were originally designed without biomarker validation but were then apparently modified to incorporate prospective biomarker validation after trial commencement, albeit only 15 (33.3%) trials reported this change. Treatment effect and primary outcome values in biomarker-negative patients were not reported in 24.4% and 40.0% trials, respectively. For 18 trials with statistically significant results in the overall population, only 7 trials reported a hazard ratio less than 0.8 in the biomarker-negative population. Conclusions Although biomarker validation in phase III trials have been increasingly used in the past decade, issues regarding changes in trial design after commencement without disclosure, underreporting of results in biomarker-negative groups, and recommending treatment in biomarker negative groups despite modest effects require substantial improvement.
Errors in Table and Figure
Authors: Erik Van Iterson, Luke Laffin, Dennis Bruemmer, Leslie Cho, Van Iterson, Bruemmer Laffin
Journal: JAMA Cardiology (2022)

Alexander J. Blood, MD, MSc; Christopher P. Cannon, MD; William J. Gordon, MD; Charlotte Mailly, BS; Taylor MacLean, MS; Samantha Subramaniam, BA; Michela Tucci, MPH; Jennifer Crossen, PharmD; Hunter Nichols, PharmD; Kavishwar B. Wagholikar, MBBS, PhD; David Zelle, BA; Marian McPartlin, BA; Lina S. Matta, PharmD, MPH; Michael Oates; Samuel Aronson, ALM, MA; Shawn Murphy, MD, PhD; Adam Landman, MD; Naomi D. L. Fisher, MD; Thomas A. Gaziano, MD, MSc; Jorge Plutzky, MD; Benjamin M. Scirica, MD, MPH
Intermittent Hypoxemia and Bronchopulmonary Dysplasia with Pulmonary Hypertension in Preterm Infants
Authors: Samuel J. Gentle, Colm P. Travers, Arie Nakhmani, Premananda Indic, Waldemar A. Carlo, Namasivayam Ambalavanan
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Bedside biomarkers that allow early identification of infants with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) are critically important, given the higher risk of death in these infants. Objectives: We hypothesized that infants with BPD-PH have patterns of intermittent hypoxemia (IH) that differ from infants with BPD without PH. Methods: We conducted a matched case-control study of extremely preterm infants from 22 weeks 0 days to 28 weeks 6 days born between 2018 and 2020 at the University of Alabama at Birmingham. BPD-PH status was determined using echocardiographic data performed after postnatal Day 28. Physiologic data were compared between infants with BPD-PH (cases) and BPD alone (control subjects). Receiver operating characteristic (ROC) analysis estimated the predictive ability of cumulative hypoxemia, desaturation frequency, and duration of intermittent hypoxemic events in the week preceding echocardiography to discriminate between cases and control subjects. Measurements and Main Results: Forty infants with BPD-PH were compared with 40 infants with BPD alone. Infants with and without PH had a similar frequency of IH events, but infants with PH had more prolonged hypoxemic events for desaturations below 80% (7 s vs. 6 s; P = 0.03) and 70% (105 s vs. 58 s; P = 0.008). Among infants with BPD-PH, infants who died had longer hypoxemic events below 70% (145 s vs. 72 s; P = 0.01). Using the duration of hypoxemic events below 70%, the areas under the ROC curves for diagnosis of BPD-PH and death in BPD-PH infants were 0.71 and 0.77, respectively. Conclusions: Longer duration of intermittent hypoxemic events was associated both with a diagnosis of BPD-PH and with death among infants with BPD-PH.
Single-cell transcriptomics of peripheral blood reveals anti-tumor systemic immunity induced by oncolytic virotherapy
Authors: Quanyou Wu, Xiao Hu, Xiaoli Zhang, Defeng Kong, Zhenrong Yang, Guoliang Li, Zhaoru Gu, Qi Zhang, Duo Wan, Shujun Cheng, Binlei Liu, Kaitai Zhang, Wen Zhang
Journal: Theranostics (2022)

Rationale: Oncolytic virus (OV) therapy as a cancer therapy that improves immune status makes it a favorable candidate for optimizing immunotherapy strategies.Existing studies have focused on characterizing the disturbance of the tumor microenvironment (TME) by OV therapy.However, the changes in systemic immunity induced by OV were largely ignored, which would prevent the further understanding and optimization of oncolytic viruses.Methods: The HSV-2-based oncolytic virus OH2 was used to treat tumor-bearing mouse models.The peripheral blood samples were then collected for single-cell RNA sequencing (scRNA-seq).The scRNA-seq data were analyzed using Cell Ranger, Seurat, and other bioinformatics tools.Key findings were further validated by ELISA, immunohistochemistry, flow cytometry, in vivo experiments, and clinical samples.Results: Our data showed that OH2 therapy effectively activated systemic immunity and induced a sustained anti-tumor immune response.One major impact of OH2 on systemic immunity was to boost Ccl5 production, which correlated with clinical response.Besides, the cytotoxic ability of peripheral cytotoxic Cd8+ T cells and mature NK cells was elevated by OH2.Further analysis revealed that the interaction of monocytes with T cells and NK cells was critical for systemic immune remodeling and activation.We also found that systemic immune responses induced by OH2 could effectively reshape the microenvironment of distant tumor lesions and inhibit their progression.Conclusions: This study is the first to comprehensively characterize the effects of OV therapy on systemic immunity, which not only sheds new light on the anti-tumor mechanisms of OH2, but also contributes to the establishment of companion diagnostics for OH2 treatment and the improvement of oncolytic therapy strategies.
Phenomapping in heart failure with preserved ejection fraction: insights, limitations, and future directions
Authors: Anthony E Peters, Jasper Tromp, Sanjiv J Shah, Carolyn S P Lam, Gregory D Lewis, Barry A Borlaug, Kavita Sharma, Ambarish Pandey, Nancy K Sweitzer, Dalane W Kitzman, Robert J Mentz
Journal: Cardiovascular Research (2022)

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous entity with complex pathophysiology and manifestations. Phenomapping is the process of applying statistical learning techniques to patient data to identify distinct subgroups based on patterns in the data. Phenomapping has emerged as a technique with potential to improve the understanding of different HFpEF phenotypes. Phenomapping efforts have been increasing in HFpEF over the past several years using a variety of data sources, clinical variables, and statistical techniques. This review summarizes methodologies and key takeaways from these studies, including consistent discriminating factors and conserved HFpEF phenotypes. We argue that phenomapping results to date have had limited implications for clinical care and clinical trials, given that the phenotypes, as currently described, are not reliably identified in each study population and may have significant overlap. We review the inherent limitations of aggregating and utilizing phenomapping results. Lastly, we discuss potential future directions, including using phenomapping to optimize the likelihood of clinical trial success or to drive discovery in mechanisms of the disease process of HFpEF.
Lecanemab in Early Alzheimer’s Disease
Authors: Christopher H van Dyck, Chad J Swanson, Paul Aisen, Randall J Bateman, Christopher Chen, Michelle Gee, Michio Kanekiyo, David Li, Larisa Reyderman, Sharon Cohen, Lutz Froelich, Sadao Katayama, Marwan Sabbagh, Bruno Vellas, David Watson, Shobha Dhadda, Michael Irizarry, Lynn D Kramer, Takeshi Iwatsubo
Journal: New England Journal of Medicine (2022)

The accumulation of soluble and insoluble aggregated amyloid-beta (Aβ) may initiate or potentiate pathologic processes in Alzheimer's disease. Lecanemab, a humanized IgG1 monoclonal antibody that binds with high affinity to Aβ soluble protofibrils, is being tested in persons with early Alzheimer's disease.